Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity: The inappropriate activation and differentiation of CD4 T cells elicits and orchestrates the onset and progression of a wide range of autoimmune diseases. Understanding CD4 T cells' intrinsic regulatory mechanisms has direct implications for the development of novel therapeutics to treat these diseases. While the protein-based signal transduction machinery downstream of T cell antigen recognition has been thoroughly studied, we have recently become aware of a novel and crucial element dictating T cell fate-microRNA (miRNA). mir-17-92 is a gene cluster encoding six different miRNAs, whose important tumor-cell-intrinsic roles in cancer have been well established. However, we have recently discovered that the mir-17-92 cluster also potentiates anti-tumor immunity in a T-cell-intrinsic manner. Furthermore, our preliminary studies indicate that mir-17-92 dictates the progression of CD4 T cell-mediated autoimmunity, principally through the activity of the cluster's mir-19b component. We aim to discover the molecular mechanism underpinning miR-19b's pro- autoimmune regulatory function, and thereby to establish miR-19b as a potential target for therapy of autoimmune diseases. PUBLIC HEALTH RELEVANCE: In this project, we are focusing on the previously unknown role of microRNA miR-19b in immunoregulation. miR-19b controls CD4 T cells' antigen response by modulating multiple signaling pathways, indicating that it may be a promising target for restoring tolerance under autoimmune conditions. One of the primary targets of this microRNA is MeCP2, the causal factor of the devastating Rett Syndrome, which provides a new angle to understand the etiology of this neuronal development disease. In addition to fundamentally advancing the fields of miRNA biology and T cell biology, this study is very likely to provide new candidate targets for oligonucleotide-based immunotherapy to combat autoimmune diseases.